Many neurological diseases are characterized by an imbalance of neuronal excitability, leading to disturbed neuronal connectivity and, in some cases, convulsive seizures. Examples of neurological diseases with deficiencies in the regulation of neuronal excitability are epilepsy, autism, spectrum disorders (ASDs), fragile X syndrome (FXS), and Alzheimer's disease (AD). Levisohn reports that there is a connection between autism and epilepsy. Epilepsia. 2007, 48 Suppl 9:33-5. Noebels reports that epilepsy and Alzheimer's dementia intersect in the hippocampal formation. Epilepsia. 2011, 52 Suppl 1:39-46.
The voltage-gated potassium channel Kv4.2 contributes to inwardly rectifying potassium currents (a.k.a. A-type currents) in the hippocampus. Kv4.2-mediated A-currents are important for action potential shaping and regulate dendritic excitability by limiting the back-propagation of action potentials. Kv4.2 plays important role in processing and transmitting information. Kv4.2 mRNA and protein levels are regulated by neuronal activity, and several different brain disorders are characterized by aberrant Kv4.2 expression. Singh et al. report Kv4.2 truncation mutation in a patient with temporal lobe epilepsy. Neurobiol Dis (2006) 24, 245-253. Gross et al. report Fragile X mental retardation protein regulates protein expression and mRNA translation of the potassium channel Kv4.2. J Neurosci (2011) 31, 5693-5698. Lee et al. report bidirectional regulation of dendritic voltage-gated potassium channels by the fragile X mental retardation protein, Neuron (2011) 72, 630-642. Hall et al. report Tau and potassium channel Kv4.2 in Alzheimer disease-related neuronal dysfunction, (2011) Neuroscience Meeting Planner. Washington, D.C.: Society for Neuroscience, 2011. Online.
MicroRNAs (miR), originally identified in plants, are typically 21-23 nucleotides in length and arise from longer precursors which are transcribed from non-protein-encoding genes. The precursors form structures that fold back on each other in self-complementary regions and are then processed by the nuclease Dicer in animals or DCL1 in plants. MicroRNA molecules interrupt translation through precise or imprecise base-pairing with their targets and are involved in gene regulation. Some miRNAs inhibit protein synthesis by binding to partially complementary 3′ untranslated regions (UTRs) of target mRNAs. Others function like siRNA and bind to perfectly complementary mRNA sequences to destroy the target transcript.
Matkovich et al., report microRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts. Circ Res (2010) 106, 166-175. Kim et al. report microRNAs that co-purify with polyribosomes in mammalian neurons. Proc Natl Acad Sci USA. 2004, 101(1):360-5.
Jimenez-Mateos et al. report silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects. Nat Med, 2012, 18(7):1087-94. See also Jimenez-Mateos & Henshall, Neuroscience, 2013, 238:218-29.
References cited herein are not an admission of prior art.